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There are questions about the molecular characterization of lung cancer leading to the identification of different molecular alterations&#44; such as <span class="elsevierStyleItalic">EGFR</span> mutations or <span class="elsevierStyleItalic">anaplastic lymphoma kinase</span> &#40;<span class="elsevierStyleItalic">ALK</span>&#41; translocations&#44; and to subsets of lung cancer disease with a distinct natural history and response to treatment&#44; together with the growing number of treatment options&#46; How can we match the right patient population to the best treatment option&#63; How much is society able to pay for the implementation of methods for molecular characterization of lung cancer disease&#63; How can we improve the cost-effectiveness of these methods&#63; Is society able to shoulder the burden of these new molecular diagnostic methods and new therapeutic drugs&#44; even if they are at some level cost-effective&#63; Will there ever be sufficient evidence to meet the challenge of cost containment&#63;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Testing patients with advanced or metastatic NSCLC for <span class="elsevierStyleItalic">EGFR</span> mutation status may help doctors to determine those who are most likely to respond to EGFR TK inhibitors&#44; tailoring therapy at diagnosis&#46; In Portugal&#44; we conducted a retrospective analysis of three major centers of the north of the country &#40;Centro Hospitalar de V&#46; N&#46; Gaia&#44; Instituto Portugu&#234;s de Oncologia &#8211; Centro do Porto&#44; Hospital de S&#46; Jo&#227;o&#41;&#44; from July 2006 to January 2011 &#91;personal data&#93;&#46; We studied 621 patients&#44; with a mean age of 65 years &#40;20&#8211;89 years-old&#41;&#44; 30&#37; of whom were female&#46; The tumours were 64&#37; adenocarcinoma and 21&#37; squamous cell carcinoma&#46; In the NSCLC population there was an <span class="elsevierStyleItalic">EGFR</span> mutation in 14&#46;3&#37; &#40;17&#46;5&#37; with adenocarcinoma and 9&#46;5&#37; with squamous cell carcinoma&#41;&#44; of which there was 6&#46;3&#37; in exon 19 &#40;43&#46;8&#37; of mutated patients&#44; mp&#41;&#44; 5&#46;3&#37; in exon 21 &#40;37&#46;1&#37; of mp&#41;&#44; 1&#46;7&#37; in exon 20 &#40;12&#46;4&#37; of mp&#41; and 1&#46;0&#37; in exon 18 &#40;6&#46;7&#37; of mp&#41;&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The work began 5 years ago in two major centers with the selection of some patients based on clinical characteristics&#46; After perceived the notion of the role of the EGFR TK inhibitors in first-line treatment for advanced or metastatic NSCLC&#44; these centers and <span class="elsevierStyleItalic">a posteriori</span> the third one began the analysis of all possible newly diagnosed patients&#46; Meanwhile&#44; there were discussions in national scientific forums&#44; involving key opinion leaders and some cooperative groups such as the Portuguese Lung Cancer Study Group&#44; about the need for <span class="elsevierStyleItalic">EGFR</span> mutation analysis&#46; These meetings played a vital role in making everyone think about the following&#58; how much lung cancer tissue is needed&#44; how to optimize the circuit from harvesting of tissue to mutation analysis&#44; how long should &#40;could&#41; we wait from harvest to analysis&#44; what pathologists and geneticists need to give to those who treat patients&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">ALK</span> rearrangement &#40;<span class="elsevierStyleItalic">ALK</span>&#43;&#41; was identified in NSCLC as an inversion in chromosome 2p with or without interstitial deletion&#44; inv&#40;2&#41;&#40;p21p23&#41;&#44; resulting in the <span class="elsevierStyleItalic">echinoderm microtubule-associated protein-like 4</span> &#40;<span class="elsevierStyleItalic">EML4</span>&#41;-<span class="elsevierStyleItalic">ALK</span> fusion product&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> This fusion oncogene&#44; which represents one of the newest molecular targets in NSCLC&#44; has a role as the key driver of lung tumorigenesis in a subset of patients<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> and can be effectively blocked by small-molecule inhibitors that target ALK&#46; <span class="elsevierStyleItalic">EML4-ALK</span> is uncommon&#44; occurring in 2&#8211;7&#37; of all NSCLC&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">8&#44;9</span></a> It is more prevalent in patients who have never smoked or who have a history of light smoking and in patients with adenocarcinomas&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;10&#44;11</span></a> In the selected populations&#44; the prevalence could be about 20&#8211;30&#37; of patients with EML4-ALK mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Nevertheless&#44; sex&#44; age and smoking status were not solid variables related with <span class="elsevierStyleItalic">ALK</span>-rearranged NSCLC&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">At present there is no standard method for detecting <span class="elsevierStyleItalic">EML4-ALK</span> mutations and various molecular techniques can be used&#46; Fluorescent <span class="elsevierStyleItalic">in situ</span> hybridization &#40;FISH&#41; is the most common method currently used and also for enrolment in a clinical trial&#44; although it is expensive and not routinely available&#46; The standardization of all preanalytical variables&#44; including tissue handling&#44; fixation and processing&#44; and the choice of anti-ALK antibodies are essential when using FISH&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Crizotinib &#40;PF-02341066&#44; Pfizer&#41; is an oral ATP competitive selective inhibitor of the ALK and MET TKs inhibiting tyrosine phosphorylation of activated ALK at nanomolar concentrations&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> The first phase I trial published&#44; evaluated 82 patients with ALK-rearranged advanced NSCLC who had received multiple previous therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> At a mean treatment duration of 6&#46;4 months&#44; the overall response rate was an impressive 57&#37; with a rate of stable disease of 33&#37;&#46; The estimated probability of 6-month progression-free survival was 72&#37;&#44; with no median for the study reach&#46; The drug resulted in grade 1 or 2 &#40;mild&#41; gastrointestinal side effects&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In an unselected NSCLC population&#44; only around 4&#37; have <span class="elsevierStyleItalic">ALK</span> rearrangements&#44; and this small proportion of ALK&#43; lung cancer patients is a major limitation for access to the related drug&#44; crizotinib&#46; How we can identify this group of patients and which ALK testing method should be employed is a major issue for discussion and research&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">It is possible to define three groups of tumors which do not harbor <span class="elsevierStyleItalic">ALK</span> rearrangements at all and could be excluded from <span class="elsevierStyleItalic">ALK</span> screening&#58; those tumors with activating <span class="elsevierStyleItalic">EGFR</span> mutations&#44; those in patients that showed an objective response to previous EGFR TK inhibitors treatments&#44; and eventually tumors without TTF-1 expression&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> But this strategy will only select patients after knowing the result of the <span class="elsevierStyleItalic">EGFR</span> mutation test or the evaluation of a response to the EGFR TK inhibitors&#44; in this way losing at least 5&#8211;7 working days &#40;for the first hypothesis&#41; or 1&#8211;3 months &#40;for the second group&#41;&#46; In relation to TTF-1 expression&#44; this marker is only negative in a minority of cases&#44; and so its relevance to selection of <span class="elsevierStyleItalic">ALK</span>&#43; patients is marginal&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">For Portugal&#44; the initial step will be to involve some of the major centers&#44; for instance in a selected population &#40;stage IV adenocarcinoma NSCLC who never smoked or were light smokers&#41;&#46; The goals will be to evaluate and optimize the circuits needed from harvest to the implementation of the test and how the clinicians obtain the result&#46; At the same time&#44; some national meetings will be necessary to discuss the importance of ALK&#44; the test of its mutation and the value of crizotinib for <span class="elsevierStyleItalic">ALK</span>&#43; patients&#46; After these initial stages&#44; probably two or three major centers will decide to do the <span class="elsevierStyleItalic">ALK</span> mutation test on all new NSCLC patients&#44; to learn more about the real incidence of the <span class="elsevierStyleItalic">ALK</span> mutation in the Portuguese NSCLC population&#46; These phases will also allow us to request crizotinib for patients with <span class="elsevierStyleItalic">ALK</span>&#43; and so acquire experience with this drug&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">At the end of the day&#44; every clinician who treats NSCLC will need to characterize the tumor histologically and&#44; particularly at the level of some molecular targets&#46; These characteristics will influence the choice of the drugs&#44; taking into account the drug related adverse events and of course survival rates&#46; This is personalizing medicine&#46;</p></span>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Personalizando a medicina &#8211; estrat&#233;gias para implementar a avalia&#231;&#227;o do re-arranjo do <span class="elsevierStyleItalic">ALK</span> no carcinoma do pulm&#227;o de n&#227;o pequenas c&#233;lulas em Portugal&#46; Rev Port Pneumol&#46; 2012&#46; <span class="elsevierStyleInterRef" href="doi:10.1016/j.rppneu.2012.04.011">http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;1016&#47;j&#46;rppneu&#46;2012&#46;04&#46;011</span>&#46;</p>"
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